ORIGINAL ARTICLE. combinations and adverse effects * DOR PÓS-OPERATÓRIA: COMBINAÇÕES ANALGÉSICAS E EVENTOS ADVERSOS

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1 Post oerative ain: analgesic * DOR PÓS-OPERATÓRIA: COMBINAÇÕES ANALGÉSICAS E EVENTOS ADVERSOS ORIGINAL ARTICLE DOLOR POSTOPERATORIO: COMBINACIONES ANALGÉSICAS Y EVENTOS ADVERSOS Silvia Regina Secoli 1, Vanessa Cristina Moraes 2, Aarecida de Cássia Giani Peniche 3, Maria de Fátima Fernandes Vattimo 4, Yeda Aarecida de Oliveira Duarte 5, Isabel Yovana Quise Mendoza 6 ABSTRACT The control f the ains and its adverse affects are in the focus of health rofessionals and institutional managers in order to otimize clinical outcomes. The objectives of this study were to analyze the revalence of medicine combination and interaction and to verify the association of this with the observed adverse effects. It was a descritive, exloratory and retrosective study. The samle was comosed by 260 atient data submitted to hemorrhoidectomy, u to 60 years old, healthy. Results showed that the mostly used medicine associations were diyrone sodium and omerazole (33.7%), dyirone sodium and ketorofen (23.6%) and cetorofen and lactulose (22.8%). It was observed that ketorofen + omerazole (=0.001) and ketorofen + lactulose (=0.03) were significantly associated with bleeding. It was observed that, exceting ketorofen, the other medicine association identified in the study showed to be safe to be used in the ost surgical eriod. KEY WORDS Pain, ostoerative. Drug interactions. Analgesics. RESUMO O controle da dor e seus eventos adversos são focos de rofissionais e gestores das instituições de saúde ara obtenção de desfechos assistenciais. O estudo teve como objetivos analisar a revalência de combinações e interações medicamentosas da teraia analgésica e verificar a associação dessa com os eventos adversos conferidos. Trata-se de estudo descritivo, exloratório e retrosectivo. A amostra foi comosta or 260 rontuários de acientes submetidos a hemorroidectomia, com idade de até 60 anos hígidos. Os resultados mostraram que as associações medicamentosas mais utilizadas foram a diirona+omerazol (33,7%), diirona+cetorofeno (23,6%) e cetorofeno+lactulose (22,8%). Observou-se que cetorofeno+ omerazol (=0,001) e cetorofeno+ lactulose (=0,03) estiveram significativamente relacionados com sangramento. Concluiu-se que, com exceção do cetorofeno, as outras associações medicamentosas identificadas no estudo se mostraram seguras ara serem utilizadas no eríodo ós oeratório. DESCRITORES Dor ós-oeratória. Interações de medicamentos. Analgésicos RESUMEN El control del dolor y sus eventos adversos se constituyen en el foco de los rofesionales y gestores de las instituciones de salud ara la obtención de resultados asistenciales. El estudio tuvo como objetivos analizar la revalencia de combinaciones y interacciones medicamentosas de la teraia analgésica y verificar la asociación de esta con los eventos adversos conferidos. Estudio descritivo, exloratorio y retrosectivo. La muestra fue comuesta or 260 historias clinicas de acientes sometidos a hemorroidectomia hasta los 60 años de edad, sanos. Los resultados mostraron que las asociaciones medicamentosas más utilizadas fueron la diirona y omerazol (33,7%), diirona y cetorofeno (23,6%) y cetorofeno y lactulosa (22,8%). Se observó que el cetorofeno+omerazol (=0,001), cetorofeno+ lactulosa (=0,03) estuvieron significativamente relacionados con el sangramiento. Se concluyó que, con exceción del cetorofeno, las otras asociaciones medicamentosas identificadas en el estudio se mostraron seguras ara ser utilizadas durante el eríodo ostoeratorio. DESCRIPTORES Dolor ostoeratorio. Interacciones de drogas. Analgésicos. * Extracted from Project Analgésicos e interações medicamentosas: uma análise do arazamento, Nurse. Ph.D. Professor at the Medical-Surgical Nursing Deartment at School of Nursing, University of São Paulo. São Paulo, SP, Brazil. secolisi@us.br 2 Nursing undergraduate student. School of Nursing, University of São Paulo. São Paulo, SP, Brazil. vc_moraes@hotmail.com. 3 Nurse. Associate Professor at the Medical-Surgical Nursing Deartment at School of Nursing, University of São Paulo. São Paulo, SP, Brasil. gghe@us.br 4 Nurse. Associate Professor at the Medical-Surgical Nursing Deartment at School of Nursing, University of São Paulo. São Paulo, SP, Brazil. nehron@us.br 5 Nurse. Associate Professor at the Medical-Surgical Nursing Deartment at School of Nursing, University of São Paulo. São Paulo, SP, Brazil. yedaenf@us.br 6 Nurse. Doctoral student at School of Nursing, University of São Paulo São Paulo, SP, Brazil. yovana@us.br Received: 09/15/2009 Aroved: 11/10/2009 Post oerative Portuguese ain: analgesic / English: combinations and adverse effects

2 INTRODUCTION Postoerative ain is the most revalent tye of acute ain exerienced by thousands of eole in the world, occurring at the rates of 29.7% and 10.9% for moderate or intense tyes, resectively. It is an autonomic, sychological and behavioral resonse that results from the comlex hysiological reaction to tissue lesion, causing a sensitive and emotional exerience that is unleasant and undesired (1-2). The somatic and sychic exression of ain can be directly or indirectly associated with the increase in morbimortality and to the length of stay, with consequent social and economic effects. The ersistence of ain, esecially when shar and rolonged, tends to increase the occurrence of adverse events, causing undesired clinical outcomes (3). Clinical and exerimental studies have addressed issues regarding the eidemiology of ain, both acute and chronic, but there is still much to be investigated in the search for safe and effective rotocols for ain management. Many of these studies derive from animal exeriments, as they resent behavioral and hysiological resonses equal to that of humans, stressing that animals should not receive a ainful stimulus greater than what is bearable in humans and that it can be interruted at any time if considered necessary. Some results in this area reiterate basic concets about the reaction to ain. It was observed that variables regarding care and individual motivation are more recisely determinants of the intensity of ain than of changes in sensorial ercetion. Therefore, there have been imrovements to mechanisms that measure the intensity of ain, which today reresent safe and effective clinical tools, considering they have become closer to the individualization setting. Nevertheless, other measures for controlling the adverse effects associated with analgesic combination should receive secial attention (4). Effective ain management is essential when roviding care for surgical atients, and the harmacological theray aims at minimizing discomfort, revent deleterious effects, facilitate the rocess of recueration and make the treatment economically feasible (3). Achieving these objectives deends on the form that the analgesic theray occurs esecially regarding the combination of medications. This measure is a current concern for rofessionals involved in health care and for institutional administrators who aim at achieving excellent outcomes. In Brazil, the interest of institutions in receiving accreditation and certification for the quality of hosital services by rograms as those roosed by the National Effective ain management is essential when roviding care for surgical atients, and the harmacological theray aims at minimizing discomfort, revent deleterious effects, facilitate the rocess of recueration and make the treatment economically feasible. Accreditation Organization (NAO) and the Joint Commission on the Accreditation of Healthcare Organizations JCAHO has roven the imortance of safety and quality in the care delivered to atients, including those involving the effective ain management (5). In the United States, rofessionals working at hositals are concerned with the evaluation of the outcomes and with the occurrence of adverse events to analgesic theraies, because ain is one of the most common symtoms and an indicator of quality (5). The safety and quality of the ain management rocess are directly related with factors such as the atient s characteristics, the aroriate indication of drug use, correct administration, the careful selection of the drugs and evaluation of their adverse events, esecially by the nursing team, which is resonsible for the full-time monitoring of atients. According to recent terminology, adverse events are understood as those that harm the atient, and are caused by using a medication, or interruting its use when necessary. These events can be avoidable, as in cases of medication errors. Others are unavoidable, such as cases of adverse drug reactions (ADR), which reresent any harmful or unwanted effect that aears after the correct administration of the medication in theraeutic doses, with the ossibility of causing harm (6). Balanced analgesia, whose rincile includes the use of a combination of analgesic drugs with the urose of imroving ain management, reducing doses and ADRs, does not always roduce desired outcomes, and can cause adverse events, which in this context are understood as the reciitation of ADR or drug interactions (DI). These events can be considered an imortant health issue, because besides causing an imact on atient safety, they imly higher costs. However, it is common for these occurrences to be inaroriately identified and reorted by health rofessionals, either because of their lack of knowledge or misinterretation of the atients signs and symtoms and comlaints. Considering that studies on this matter remain inciient, the undesired signs and symtoms, which are mainly identified by the nursing team, reresent imortant indicators of the resonses to medications. Therefore, the resent study was erformed with the urose to analyze the rofile of the analgesic theray in the ostoerative (PO) eriod regarding the revalence of combinations and otential DI, and verify the associations between signs and symtoms that indicate adverse events in drug combinations. METHOD This is a descritive, exloratory and retrosective study. The oulation consisted of 260 medical records of Post oerative ain: analgesic

3 atients submitted to hemorrhoidectomy between January and December 2004 at a rivate general hosital in the city of São Paulo. The convenience samle consisted of adults with 60 years of age or less, healthy according to the hysical evaluation established by the American Society of Anesthesiologists ASA at the levels I and II, submitted to elective closed hemorrhoidectomy and by the same coloroctology team. Data collection was erformed after being aroved by the Ethics Committee at the Institution, using a form containing atient identification information (age, gender, use of medications at home, smoking and drinking habits, and reexisting diseases), harmacological treatment (medication, dose, administration route and frequency) and the signs and symtoms reorted in the nursing notes and on the medical evolution sheet. The drug combinations, when reorted, were analyzed in terms of the resence or absence of DI, according to secialized literature (7-8). The otential ADRs were identified according to the Drug Information Handbook International (9). Signs and symtoms were analyzed using the medical records of atients who were in the first PO day (1PO), exclusively. This way, in this art of the analysis the oulation consisted of 239 medical records. Patients in immediate PO (POI) were excluded from this study to avoid any interference from the anesthetics in the atients signs and symtoms. Data analysis was erformed using the rogram SPSS 12.0, and the statistical tests used were the Kolmogorov- Smirnof and Pearson s Chi-square at a 5% significance level. RESULTS It was verified there is a redominance of female atients (54.5%), with an average age of 44.4 years, who used medications at home (54.1%), did not drink or smoke (65.4%), did not have any reexisting comorbidity (64.2%), classified as ASA I (73.2%), used re-anesthetic (96.9%) and received general anesthesia (99.2%). During the POI and 1PO eriods, resectively, an average of 4.08 and 3.78 medications was administered er day, in addition to 2.41 analgesics. There were 1.43 signs and symtoms during POI er atient. It was observed that ain (54.4%) and bleeding (48.1%) were the most revalent signs and symtoms among atients during 1PO (Table 1). During POI and 1PO, the most rescribed medications were: diyrone (79.6%), omerazole (66.5%) and ketorofen (66.1%). It was observed that use of diyrone (85.4%) and ketorofen (74.1%) was maintained during 1PO. Table 1 - Patient distribution according to the occurrence of signs and symtoms - São Paulo Signs and symtoms Pain Bleeding Abdominal ain Nausea Vomiting N Patients % Eighteen drug combinations were identified. Most included diyrone + omerazole (33.7%) and diyrone + ketorofen (23.6%), (Table 2). Table 2 - Patient distribution according to drug combinations existing in the first ostoerative eriod - São Paulo Drug combination Total N % Diyrone + Omerazole Diyrone + Ketorofen Ketorofen + Lactulose Diyrone + Cefoxitin Ketorofen + Omerazole Diyrone + Lactulose Rofecoxib + Lactulose Diyrone + Rofecoxib Ketorofen + Ranitidine Meeridine + Lactulose Oxycodone + Lactulose Ketorofen+ Meeridine Lactulose + Omerazole Diyrone + Bromoride (Adihenine+Diyrone+Promethazine) Omerazole Meeridine + Omerazole Cefoxitin + Omerazole Ketorofen + Oxycodone These combinations were analyzed for the existence of DI among their agents. Only one DI was found between ketorofen + ranitidine of low severity and delayed onset. Table 3 lists signs and symtoms and the combination between analgesics and adjuvants, and shows there was a significant association between the symtom of ain and use of the combinations diyrone+omerazole ( = 0.01) and lactulose+ketorofen ( = 0.01). There was a statistically significant association between the combination of ketorofen+omerazole and bleeding (=0.001); and lactulose+ketorofen and bleeding (=0.03) Post oerative ain: analgesic

4 Table 3 - Patient distribution according to signs and symtoms and drug combinations - São Paulo Signs and Symtoms Pain Bleeding Nausea Vomiting Abdominal ain Ketorofen + Diyrone Omerazole + Diyrone Lactulose + Diyrone Omerazole + Ketorofen Lactulose + Ketorofen Patients who used NSAI+AO had a significantly greater number of cases of bleeding comared to the grou that used NSAI+NSAI (=0.001) (Table 4). Table 4 - Patient distribution according to signs and symtoms and use of nonsteroidal anti-inflammatory drug combinations (NSAI) and between NSAI and oioid analgesics (OA) - São Paulo Signs and symtoms NSAI+NSAI NSAI+AO Pain Bleeding Nausea Vomiting Abdominal ain NSAI=nonsteroidal anti-inflammatory drug, OA = oioid analgesic DISCUSSION The resent study found that the most used drug classes were analgesics and agents that can comromise the digestive system, both with the urose of reducing discomfort and relieving ain in atient submitted to hemorrhoidectomy. The intensity of ain among these atients, usually moderate to intense, was often related to the attern of bowel functioning, thus requiring imortant adjuvant measures, as the use of laxatives (3,10). As for analgesics, it was found that diyrone and ketorofen were the most used. Diyrone is currently considered one of the main analgesics, whose clinical efficacy in ostoerative ain has been reorted in several studies, esecially as an adjuvant in surgeries such as hemorrhoidectomy (3,10-13). Studies show that high doses of diyrone are similar to the administration of OA such as tramadol and meeridine (14). Ketorofen is also often stated for ain management in PO of hemorrhoidectomy atients (3). NSAI are the most common drugs used for ain management in PO. In the United States NSAI reresent over 111 million rescritions. They are strong analgesics that can be used in single- and multi-modal aroaches, including recovering analgesia. The reference of this class of medications is due to fact that they do not induce sedation or resiratory deression and can significantly reduce the need for OA. In addition, atients treated with NSAI demonstrate a greater reduction in the intensity of ain and need little additional analgesia (14-15). Clearly, undesirable effects such as gastric bleeding and acute renal lesion should not be disregarded when indicating these agents. In terms of drug combinations, it was found that the combination between analgesics with the same action mechanism, i.e., inhibition of cyclooxygenases (COX) whether it is 1, 2 or 3, (diyrone+ketorofen; diyrone +rofecoxibe), as verified in the resent study, can increase the occurrence of ADR such as abdominal ain and the risk of bleeding (16-17). Nevertheless, although there was a greater number of abdominal ain cases among atients who used NSAI, no statistically significant difference was found between those who received the NSAI+AO combination. More than half of atients (54.0%) reorted the occurrence of ain, which can be associated with the low frequency in the use of multi-modal aroaches that include Post oerative ain: analgesic

5 NSAI+AO. In addition, revalent combinations as the ones identified (NSAI+NSAI) do not imrove the additional analgesic effect, since these harmaceuticals resent ceiling effect (3,9). About one-third of the oulation (31.4%) reorted abdominal ain, desite the co-rescrition of gastric secretion inhibitors. This frequency can be considered relatively high if comared to other studies that evaluated ulceration and bleeding after chronic use of NSAI (16-17). On the other hand, the low frequency of other gastrointestinal system symtoms such as nausea and vomiting occurred due to the restricted use of OA. It is a fact that, regardless of the frequency, the occurrence of any of these signs or symtoms can increase the length of stay and, indirectly, exose atients to the risk of adverse events such as ADRs and DIs, esecially in situations involving the existence of comorbidities and the use of chronic medication. The identified combinations could, initially, affect the attern of agent absortion, considering that most combined NSAI and anti-ulcer drugs. NSAI are weak acids, which in contact with an alkaline H (rovided by the use of H 2 antagonists and roton um blockers) become more ionized, which makes it more difficult for the drug to cross the lasma membrane, delaying the absortion of NSAI. Nevertheless, literature shows that ketorofen was the only NSAI involved in DI, erhas due to the high bond to lasma roteins (99%), which combined with ranitidine. This DI, whose mechanism is unknown, is classified as being of low severity, i.e., the interaction resents limited effects that usually do not require treatment (8-9). A significant association was observed between the occurrence of ain and the use of the combinations diyrone +omerazole (=0.01) and ketorofen+lactulose (=0.01). This fact can be exlained by the alteration of the gastrointestinal tract H, with a consequent delay in the absortion of NSAI and in the analgesic effect. In contrast, there was no association between incision bleeding and the use of the ketorofen+diyrone combination, though it could be exected, because both agents, at higher and lower levels, can cause blood dyscrasias and increase the risk for ADR, when in combination. Lesion bleeding was associated with using ketorofen +omerazole (=0.001) and ketorofen+lactulose (=0.03). It is likely that ketorofen, in both cases, increased the risk for hemorrhage due to the inhibition of latelet function, thus increasing the occurrence of surgical wound bleeding (9). Furthermore, in cases of the ketorofen+lactulose combination, bleeding may occur due to straining during defecation, which is stimulated by the use of laxatives. In regard to ostoerative ain management, the fact that the most commonly used analgesics (NSAI) do not resent DI, aart from ketorofen, is very ositive because these agents are frequently combined to other medications during the PO eriod. However, ADR tracking, esecially for NSAI, should be systematically monitored by the health team because the drugs involved in the undesired occurrences found in this study belonged to this drug class. The revalent signs and symtoms (ain, bleeding and abdominal ain) associated with drug combinations can be indicative of adverse events, desite the fact that the analyzed samle was small and restricted to a articular surgical rocedure, and the fact it is a retrosective study, which limited the researchers to working with reviously registered information. In this sense, it is suggested that further rosective studies be erformed to refute or corroborate the findings of the resent study and increment information to imrove atient care quality regarding ostoerative ain management. CONCLUSION The analysis of the revalence of drug combinations and otential DI existing in the analgesic theray during the PO eriod, and of associations between signs and symtoms indicative of adverse events with the drug combinations ermitted to draw the following conclusions: ain (54.4%) and bleeding (48.1%) were the signs and symtoms indicative of revalent adverse events among atients during 1PO; 46.8% of atients received drug combinations with NSAI (diyrone or ketorofen) and roton um blockers (omerazole); only one low severity delayed onset DI was found for ketorofen+ranitidine, used by 2.8% of the samle; a significant association was found between the resence of ain and the use of diyrone +omerazole (=0.01) and lactulose+ketorofen (=0.01); and between the occurrence of bleeding and the use of ketorofen+omerazol (=0.001) and lactulose+ketorofen (=0.03). In nursing, although signs and symtoms are considered intermediate outcomes for health care evaluation, they are essential in ostoerative ain management, because they can hel measure the success or failure of commonly used drug combinations. Therefore, a systematic evaluation of atients submitted to analgesic theray could hel the medical team to adjust the atient s theraeutic regimen, suort the roosition of reventive interventions, with the urose of avoiding adversities, and contribute with the service of harmacovigilance in terms of reorting adverse events Post oerative ain: analgesic

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